Ablation of the inflammatory enzyme myeloperoxidase mitigates features of Parkinson's disease in mice

Dong-Kug Choi, Subramaniam Pennathur, Celine Perier, Kim Tieu, Peter Teismann, Du Chu Wu, Vernice Jackson-Lewis, Miquel Vila, Jean-Paul Vonsattel, Jay W Heinecke, Serge Przedborski

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196 Citations (Scopus)

Abstract

Parkinson's disease (PD) is characterized by a loss of ventral midbrain dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Inflammatory oxidants have emerged as key contributors to PD- and MPTP-related neurodegeneration. Here, we show that myeloperoxidase (MPO), a key oxidant-producing enzyme during inflammation, is upregulated in the ventral midbrain of human PD and MPTP mice. We also show that ventral midbrain dopaminergic neurons of mutant mice deficient in MPO are more resistant to MPTP-induced cytotoxicity than their wild-type littermates. Supporting the oxidative damaging role of MPO in this PD model are the demonstrations that MPO-specific biomarkers 3-chlorotyrosine and hypochlorous acid-modified proteins increase in the brains of MPTP-injected mice. This study demonstrates that MPO participates in the MPTP neurotoxic process and suggests that inhibitors of MPO may provide a protective benefit in PD.
Original languageEnglish
Pages (from-to)6594-6600
Number of pages7
JournalJournal of Neuroscience
Volume25
Issue number28
DOIs
Publication statusPublished - 15 Jul 2005

Keywords

  • 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • amyotrophic lateral sclerosis
  • animals
  • brain
  • corpus striatum
  • dopamine
  • drug evaluation, preclinical
  • enzyme induction
  • humans
  • Huntington disease
  • hypochlorous acid
  • male
  • mesencephalon
  • mice
  • mice, inbred C57BL
  • mice, knockout
  • nerve tissue proteins
  • neurons
  • oxidative stress
  • Parkinson disease
  • parkinsonian disorders
  • peroxidase
  • messenger RNA
  • reverse transcriptase polymerase chain reaction
  • tyrosine

Cite this

Choi, D-K., Pennathur, S., Perier, C., Tieu, K., Teismann, P., Wu, D. C., Jackson-Lewis, V., Vila, M., Vonsattel, J-P., Heinecke, J. W., & Przedborski, S. (2005). Ablation of the inflammatory enzyme myeloperoxidase mitigates features of Parkinson's disease in mice. Journal of Neuroscience, 25(28), 6594-6600. https://doi.org/10.1523/JNEUROSCI.0970-05.2005